Saikosaponins aggravate mitochondrial damage and senescence of cholangiocyte in cholestatic liver diseases by inhibiting protective autophagy.

BACKGROUND

Cholestasis is a common pathological feature in multiple liver diseases which is characterized by toxic bile acid accumulation and liver injury. Emerging evidence indicated that total saikosaponins (TSS) from Radix Bupleuri (RB) could disrupt autophagic flux, probably exacerbating cholestatic liver injuries and warranting further investigation.

PURPOSE: This study aims to investigate whether TSS promote cholestatic liver injury by impairing protective autophagy in liver and underlying mechanisms.

METHODS

Abcb4-/- mouse was used to evaluate the effects of TSS on cholestatic liver injuries. Bulk RNA sequencing (RNA-seq) of livers was performed to reveal the underlying mechanisms.

RESULTS

TSS treatment significantly intensified ductular reaction, inflammation, and fibrosis in Abcb4-/- mice. Mechanistically, excessive taurocholic acid (TCA), the predominantly accumulated-conjugated primary bile acid during cholestasis induced the opening of mitochondrial permeability transition pore (mPTP), leading to the leakage of cytochrome C and DNA from mitochondria in cholangiocytes. By inhibiting autophagosome-lysosome fusion, TSS hindered the clearance and recycling of damaged mitochondria and remarkably enhanced mitochondrial fission. Subsequently, the released DNA-derived from damaged mitochondria drove senescence and senescence-associated secretory phenotype (SASP) in cholangiocytes to promote cholestatic liver injuries.

CONCLUSION

Our study demonstrates that TSS exacerbates cholestatic liver injury by suppressing protective autophagy, and engenders a novel therapeutic insight for cholestatic liver diseases by targeting autophagy activation or cholangiocytes senescence. Meanwhile, it underscores the need for heightened clinical caution regarding the use of autophagy-inhibiting medications such as saikosaponins or its analogues in patients with cholestatic liver diseases.